Positron emission tomography (PET) is a technology of nuclear medicine in which radiopharmaceutical agents are used that are formed from biologically relevant molecules that are labeled with positron-emitting isotopes. PET is used to study metabolic processes and physiological processes. Based on the use of analysis of radiation of short-lived radioisotopes of elements that are found in the human body, PET delivers additional information to other diagnostic processes, such as, for example computer-based tomography or examinations using magnetic resonance. PET radiopharmaceutical agents participate in biochemical reactions of the body with a dose that is not critical for humans.
The utility of PET depends essentially on the availability of nontoxic radiopharmaceutical agents. Fluorine-18 (18F) has proven to be one of the preferred radioisotopes because its decay energy of 0.64 MeV makes possible a high inherent resolution during PET measurements. 18F, moreover, has an advantageous half-life of 109.8 minutes. In the past, especially 2-[18F]fluoro-2-desoxy-D-glucose ([18F]FDG) has been successfully used. This labeling substance is used worldwide for the most varied applications. [18F]FDG is a sugar compound that is labeled with 18F and that can be easily administered to a patient. [18F]FDG is easily processed by growing cancer cells, the brain or cardiac muscles. The described properties of [18F]FDG have led to its being successfully used in nuclear medicine. The use of PET in clinical applications has led to development of devices for synthesizing radiopharmaceutical agents such as [18F]FDG.
The publication by N. Satyamurthy: Electronic Generators for the Production of Positron-Emitter-labeled Radiopharmaceutical Agents: Where Would PET Be Without Them? Clinical Positron Imaging, Vol. 2, No. 5, pages 233-253, 1999, describes in survey form various devices for automated FDG synthesis.
Document U.S. Pat. No. 5,932,178 discloses an FDG synthesis module with a column that is filled with a polymer-supported catalysis resin. Document U.S. Pat. No. 5,808,020 describes an optical reaction cell and a light source for processes for synthesis of 18F-labeled radiotracers using [18F]fluoride.
Document WO 02/36581 describes novel radiopharmaceutical agents that bind to the CCR1 receptor, which occurs in conjunction with Alzheimer's disease in the brain areas of patients.
Based on the search for novel, suitable radiopharmaceutical agents that are based on new synthesis processes, there is a demand for devices that can be used for the synthesis of radiopharmaceutical agents.
The Invention
The object of the invention is therefore to devise an improved device and an improved process for nucleophilic fluorination that makes possible application-dependent synthesis of nucleophilically fluorinated substances in a manner that is suitable for flexible clinical applications.
This object is achieved according to the invention by a device according to independent claim 1 and a process according to independent claim 9.
A device that is used for nucleophilic fluorination of a substance, especially for synthesis of an 18F-labeled substance for examination using a positron emission tomograph, comprises an anion exchange device for extraction of [18F]fluoride ions by means of adsorption from a target fluid, and the anion exchange device can be charged via a supply device with the target fluid, and a measurement device with a measurement chamber for measuring the initial radioactivity of the [18F]fluoride ions. Here, the anion exchange device is located at least partially in the measurement chamber of the measurement device. This has the advantage that the initial radioactivity of the [18F]fluoride ions can be measured while they are in the anion exchange device. Because of an additional collecting vessel for the target fluid, no losses occur.
In one feasible further development of the invention, there is a vessel for holding a nucleophilically fluorinated reaction product, the vessel being located at least partially in the measurement chamber of the measurement device in order to measure the radioactivity of the nucleophilically fluorinated reaction product. In this way, the initial radioactivity and the radioactivity of the reaction product can be measured using an individual measurement device. Both measurements can be taken without the need to move or re-arrange parts of the measurement device.
The accuracy of the radioactivity measurements is improved in one feasible configuration of the invention in that the measurement device is a measurement device that can be calibrated. This has the advantage, moreover, that in a subsequent measurement, background radioactivity due to residues in the measurement chamber can be eliminated by compensation of the background radioactivity as measured value adulteration.
A compactly executable measurement device that is provided with the required accuracy can be formed in one advantageous further development of the invention in that the measurement device is an activity meter. An activity meter is used for fast and accurate determination of the radioactivity of radionuclides. Important advantages of radioactivity measurement with an activity meter consist in 4-π measurement geometry, the large linear measurement range and the nuclide-specific calibration.
The use of the device for nucleophilic fluorination, in which purity of the reaction product that is as great as possible is necessary, is made possible in one advantageous embodiment of the invention in that there is an HPLC device (HPLC—“High Performance Liquid Chromatography”) with an HPLC column for purifying a reaction mixture. Such an HPLC device that is also called preparative HPLC is used for isolation and purification of components. In nucleophilic reactions, reaction mixtures often occur that can be separated using the HPLC device.
One preferred development of the invention can provide that the HPLC device comprises a sample feed valve that is connected to a coupling line for charging the metering device; the sample feed valve is coupled via a waste line to a waste tank; a fluid sensor device is connected upstream from the sample feed valve for detecting the reaction mixture in the coupling line; and the sample feed valve is made to be controllable so that the sample feed valve is set in the initial state in order to form, via the metering device, a fluid connection between the coupling line and the waste line, when using the fluid sensor device the reaction mixture in the supply line is detected, and the sample feed valve is switched into an injection state for charging the HPLC column in order to form a fluid connection between the metering device and the HPLC column in the injection state, when the reaction mixture is no longer being detected in the supply line using the fluid sensor device. Using this configuration prevents the fact that when the HPLC device is being charged with the reaction mixture, air that is in the lines connected upstream from the HPLC device is transferred into the metering device of the HPLC device before the reaction mixture travels into these lines; this could adversely affect the yield of the isolation and the effectiveness of separation in the HPLC device.
One feasible configuration of the invention can provide for formation of a direct coupling between the fluid sensor device and a reaction vessel by means of the coupling line. Direct coupling reduces the probability of losses in the transfer of the reaction mixture.
One feasible embodiment of the invention can provide for the HPLC device to comprise a purification device with a UV detector device and a gamma detector device that follows the UV detector device for purifying the reaction mixture using the UV detector device and then using the gamma detector device. This arrangement makes it possible to isolate a radioactive peak such that as few chemical impurities as possible with the corresponding UV absorption are contained, and the losses of the radioactive end product can be minimized.
The features from the dependent claims of the process for nucleophilic fluorination of a substance have the advantages named in conjunction with the pertinent features in the dependent device claims.